Mast cells are known to play an important role in allergic and immune responses through the release of a number of mediators, such as histamine, leukotrienes, cytokines, prostaglandin D2, etc.
Prostaglandin D2 (PGD2) is the major metabolite produced by the action of cyclooxygenase on arachadonic acid by mast cells in response to allergen challenge (R. A. Lewis et al; J. Immunol., 1982, 129 (4), 1627) and is also produced by macrophages and Th2 lymphocytes.
PGD2 has been detected in high concentrations in patients with systemic mastocytosis (J. L. II Roberts et al; Trans. Ass. Am. Phys., 1980, 93, 141), allergic rhinitis (R. M. Naclerio et al; Am. Rev. Respir. Dis., 1983, 128 (4), 597; M. S. Brown et al; Arch. Otolarynol. Head Neck Surg., 1987, 113 (2), 179; B. Lebel et al; J. Allergy Clin. Immunol., 1988, 82, 869) and bronchial asthma (J. J. Murray et al; N. Engl. J. Med., 1986, 315 (13), 800).
PGD2-driven exaggerated allergic inflammation and inflammatory responses have been demonstrated in mice and rats. Transgenic mice over expressing PGD2 synthase exhibit an enhanced pulmonary eosinophilia and increased levels of Th2 cytokines in response to allergen challenge (Y. Fujitani et al; J. Immunol., 2002, 168 (1), 443). Also, exogenously administered CRTH2 agonist 13,14-dihydro-15-keto-PGD2 (DK-PGD2) enhances the allergic response in sensitized mice (I. Spik et al; J. Immunol, 2005, 174 (6), 3703). In rats intratracheal administration of CRTH2 agonists causes pulmonary eosinophilia whereas a DP agonist (BW 245C) or a TP agonist (1-BOP) have no effect (Y. Shirashi et al; J. Pharmacol. Exp. Ther., 2005, 312, 954).
PGD2 mediates its effects through two high affinity 7-transmembrane receptors, the PGD2 receptor (DP) (Y. Boie et al; J. Biol. Chem., 1995, 270, 18910) and the chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) (K. Nagata et al; J. Immunol, 1999, 162, 1278).
It has been shown that CRTH2 is expressed on cell types associated with allergic inflammation, such as Th2 cells, basophils and eosinophils and that its activation by PGD2 triggers the migration of these cell types (H. Hirai et at; J. Exp. Med., 2001, 193, 255). CRTH2 was also reported to play a major role in neutrophil and eosinophil recruitment in a model of contact dermatitis (K. Takeshita et al; Int. Immunol., 2004, 16, 947-959).
Allergic asthma and allergic rhinitis are diseases that currently affect about 10% of the population, and this number appears to be increasing (R. K. Bush, Handbook of asthma and rhinitis. 1st ed. (1997), Abingdon: Blackwell Science, 270). Numerous classes of pharmaceutical agents are widely used to treat these diseases, for example, antihistamines, decongestants, β2 agonists, anticholinergics, methylxanthines, cromolyns, corticosteroids, and leukotriene modulators. Generally, the usefulness of these agents is limited by side effects and low efficacy. Accordingly, there is a critical medical need to identify pharmaceutically active compounds that interfere with key steps of the inflammatory and immunological processes that contribute to these disease states, and other inflammatory conditions.
The observations summarized above suggest that CRTH2 antagonists (P. Norman, Exp. Opin. Ther. Patent, 2005, 15(12), 1817) may have valuable properties for the treatment of diseases mediated by PGD2.